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Background Paraneoplastic neurological syndromes (PNS) are a group of syndromes that affect the central and peripheral neuromuscular system in association with cancer. Specific antibodies may assist in the diagnosis of PNS. The antibodies tested can be classified into those directed against intracellular neuronal proteins (“well characterized” PNS: Hu, Yo, RI, CV2, amphiphysin, Ma1, Ma2) and those directed against neural surface antigens (autoimmune encephalitis syndromes: NMDA, AMPA, LGI1, CASPR2, GABAR). We aimed to characterize patients with unexplained neuropsychiatric symptoms, in whom positive PNS antibodies were detected in the Sheba medical center, a large referral hospital. Methods Clinical and demographic data of patients with positive PNS antibodies were collected during the years 2002–2016. Antibodies were tested by either Line immunoassay or by cell-based indirect immunofluorscent assay. Results During the follow up of 14 years, 4010 PNS tests were performed in patients with unexplained neuropsychiatric symptoms. Seventy-two were found to be positive; among them we had full clinical data access to 44. The most frequent antibodies were anti-Hu (31.8%), anti-Yo (18.2%), anti-CV2 (13.6%), and anti-NMDA (9.1%), and the most common cancers were small-cell lung (SCLC) and ovarian cancers. In the well characterized paraneoplastic group, cancer was diagnosed in 55.9% of the patients, and in the autoimmune encephalitis group, 40.0% were diagnosed with cancer. A positive correlation between antibody titer and the presence of cancer was found. Ninety percent of the tests in patients who were found positive were ordered by a neurologist or neuro-oncologist. Conclusions The titers of PNS auto-antibodies can predict cancer in patients whom anti-PNS antibodies are tested. In addition, consultation with a specialist should be considered before this test is ordered.

Clinical and experimental data support a critical role for inflammation in cardiovascular disease. The purpose of the current study was to examine the relation between an inflammatory marker, neutrophil-to-lymphocyte ratio (NLR), and incident atrial fibrillation (AF) in asymptomatic adults. We investigated 21,118 self-referred men and women who were annually screened in a tertiary medical center. All subjects were free of AF at baseline and had their serum NLR calculated at the first annual visit. Subjects were divided into 2 groups based on their baseline NLR: Low (2.83; n = 17,524) and high (≥2.83; n = 3,594; Upper Sextile). The primary endpoint was new onset AF during follow-up. Mean age of study population was 48 ± 10 years and 72% were men. A total of 563 (2.7%) incident events occurred during an average follow-up of 7.5 ± 5 years. Unadjusted Cox regression analysis demonstrated that each 1 unit increase in NLR was associated with a significant 14% increase in risk of occurrence of a first AF event (95% confidence interval 1.06 to 1.23, p0.001) and 20% increased risk of death. Kaplan-Meier's survival analysis showed that the cumulative probability of incident AF was significantly higher among subjects with high NLR compared with low NLR group (p = 0.006). Interaction analysis with adjustment to clinical parameters showed that NLR-related risk was age-dependent, such that in the younger age-group (=50 years) high NLR group had two folds increased risk for AF event compared with low NLR group (95% confidence interval 1.08 to 3.51; p = 0.027) whereas among older subjects the rate of events was similar between both NLR groups (p = NS; p for interaction = 0.024). In conclusion, our findings suggest that high NLR is associated with increased risk of new onset AF. This finding is more pronounced among young adults.

To evaluate the association between inflammatory back pain (IBP) features, acute and structural MRI findings suggestive of sacroiliitis, and diagnosis of spondyloarthritis (SpA). Data from 224 patients who underwent MRI for suspected sacroiliitis (2005–2015) was retrospectively reviewed by an expert rheumatologist for the presence of IBP features and for clinical standard of reference diagnosis. A telephone questionnaire was performed in cases of missing data. Acute and structural MRI parameters were scored by an experienced radiologist for the presence of sacroiliitis using the Assessment of Spondyloarthritis International Society (ASAS) criteria, Berlin score, and observer’s global impression (GI) scores. Association between IBP features and MRI scores, and odds ratio for SpA diagnosis, were calculated. One hundred ninety-three subjects were included (119 F:74 M, mean age 39.7 ± 15.6, mean follow-up 49 ± 18 months). Fifty-two (26.9%) subjects were diagnosed with SpA. IBP scores were significantly higher in SpA patients (p

Objective FMF is an autoinflammatory disease of genetic origin. Colchicine is the mainstay of treatment for the prevention of attacks and long-term complications but 5–10% of FMF patients are resistant to colchicine therapy. The aim of our study was to investigate the real-life safety and efficacy of anakinra in a cohort of patients with colchicine-resistant FMF. Methods In this retrospective study, patients treated with anakinra for colchicine-resistant FMF between 2010 and 2018 were identified using the computerized database of Sheba Medical Center and enrolled in the study. Data from structured clinical files were analysed to evaluate the efficacy and safety outcomes. To assess efficacy, we used the Global Assessment Score (GAS), a measure comprised of three different domains: number of attacks per month, duration of attacks and number of sites involved in the attacks. Reported adverse events were compiled. Results A total of 44 patients (24 female) were treated with anakinra. Of these patients, 75% were homozygous for the M649V mutation. The mean duration of treatment was 18 months. The GAS decreased significantly from 6.6 (IQR 5.3–7.8) before treatment to 2 (IQR 0–4.2) while on treatment (P Conclusion Treatment with anakinra is beneficial for the majority of colchicine-resistant FMF patients and is relatively safe.

BACKGROUND Data on the association between AF and fitness are conflicting. OBJECTIVES The aim of this analysis was to investigate the association between fitness, obesity and incidence of atrial fibrillation (AF) among apparently healthy non-athlete adults. METHODS We investigated 20 410 self-referred subjects who were annually screened in a tertiary medical centre. All subjects were free of AF and completed maximal exercise stress test according to the Bruce protocol at baseline. Fitness was categorised into age- and sex-specific quintiles (Q) according to the treadmill time. Subjects were categorised to low (Q1-Q2) and high fitness (Q3-5) groups. The primary end point was new-onset AF during follow-up. RESULTS Mean age was 48 ± 10 years and 72% were men. A total of 463 (2.3%) events occurred during an average follow-up of 8 ± 5 years corresponding to an AF event rate of 0.3% per person year. Univariate and multivariate models showed that AF risk was similar in both fitness groups. However, AF event rate was 0.55% per person year among high fitness obese subjects, compared with 0.31% for low fitness obese subjects (P

Inflammatory myopathies are a clinically diverse group of diseases, in which the detection of particular autoantibodies may facilitate diagnosis, treatment, and prognosis. The aim of this report is to summarize our experience with specific autoantibody testing in patients with inflammatory myopathies. Data were collected over the last decade in the Autoimmune Center of the Sheba Medical Center, a tertiary referral hospital. Data regarding patients' positive for autoantibodies against Jo-1, PL-7, PL-12, SRP, Mi-2, Ku, and PM-Scl antigens were retrospectively collected. Patient demographics, clinical characteristics, and mortality were recorded. Descriptive statistics (mean, standard deviation, frequency, and percentage) were calculated. A total of 507 patients were surveyed for sclero-poly-synthetase antibodies, as part of the diagnostic workup of myositis/myalgia or interstitial lung disease. Forty-three patients were found positive for one or more of the abovementioned antibodies, and 23 of them (53.49%) had interstitial lung disease (ILD). Four patients were positive for anti-PL-7, three of them had ILD and Raynaud's phenomenon. Five patients were positive for anti-Ku, and four of them had both arthritis and Raynaud's phenomenon. Nine patients were positive for anti-Mi-2, and six of them were given diagnosed with dermatomyositis. Ten patients were positive for anti-SRP, and six of them had cancers of various types. Our results reiterate the previously recognized associations between anti-Mi-2 and dermatomyositis, anti-Ku and Raynaud's phenomenon, and between anti-PL-7 and ILD. In addition, our data support an association between anti-SRP autoantibody positivity and malignancy, which calls for further investigation.

Sjogren's syndrome is associated with chronic cough, but sicca symptoms are missing from cough evaluation guidelines. We evaluated patients with unexplained cough for undiagnosed Sjogren's syndrome. Patients referred to our pulmonary clinic (Sheba Medical Center, 2009 to 2012) with unexplained cough and concomitant dry eyes were selected for evaluation. Unexplained cough was defined as chronic cough of unknown etiology despite algorithm-based evaluation and treatment. Patients were evaluated in a dedicated clinic by a pulmonologist, rheumatologist, and ophthalmologist specializing in autoimmune disease. Patients completed the Leicester Cough Questionnaire, spirometry, antibody testing for anti Ro/La, ophthalmologic examination with visual acuity, eyelid, ocular surface fluorescein staining, tear break-up time and Schirmer's test, full slit lamp, and fundus examinations. Four-year follow-up was conducted by telephone questionnaire. We identified 24 patients among which 22 (21 females) agreed for evaluation. Eight patients (36%), seven initially, and one during follow-up were diagnosed with Sjogren's syndrome (SS) (six secondary and two primary SS). At 4-year follow-up, cough tended to persist and improve in only 37% with SS. These include 2 (Scl and RA) who received rituximab and 1 (stage 1 sarcoidosis) with spontaneous improvement. In contrast, cough improved in most (64%) patients without SS; the majority (eight/nine) report intensified disease-specific treatment (five allergic and three GERD). We describe patients in whom unexplained chronic cough was associated with dry eyes. Focused workup revealed undiagnosed Sjogren's syndrome in 36%. Dry eyes, with or without SS, is under-recognized and should be added to diagnostic algorithms for unexplained cough.

Objective Familial Mediterranean fever (FMF) is an autoinflammatory disease manifested with recurrent serosal inflammation. The association between FMF and malignancy has not been described. The aim of this study was to estimate cancer risk in a large single-institution cohort of FMF patients. Methods The study cohort consisted of 8,534 FMF patients registered in the Israel National FMF Center at Tel Hashomer, Israel. We linked the study cohort to the database of the Israel National Cancer Registry using the national identity number. Cancer incidence in FMF patients was determined and stratified by age and gender. Standardized incidence ratios (SIR) for cancers were calculated. Results Among 8,534 FMF patients (4,400 men, 4,134 women), 350 developed cancer during the years 1970-2011. Overall cancer risk among patients with FMF was significantly lower than that expected in the following gender and ethnic groups of the Israeli population: males of Jewish ethnicity SIR 0.66, CI 95% [0.55-0.77], p

Background Data on the functional impact of anemia on cardiorespiratory fitness (CRF) and survival in healthy individuals are limited. Our aim was to evaluate the association between anemia thresholds, low CRF, and survival in otherwise healthy adults. Methods Study population included 16 334 apparently healthy subjects attending annual periodic health screening examinations (71 200 annual visits), including exercise stress testing (EST). Anemia was defined by the World Health Organization (WHO) or Beutler and Waalens’ (BW) criteria. Low CRF was defined as the lowest fitness quintile according to the Bruce protocol. Results The mean age was 46±10 years, and 70% were men. Mean Hb levels were 13±1 and 15±1 among women and men, respectively, with higher proportion of anemia among women. The majority of anemic subjects had mild anemia. When analyzing repeated annual visits, anemia was associated with a significant 39% and 64% increased risk of low CRF according the WHO and BW criteria only in women (n=18 672). Baseline anemia at first visit was associated with 2.6- and 1.9-fold increased risk of all-cause mortality using the WHO and BW criteria, exclusively in men (n=11 511). Conclusions Overall, the functional and prognostic impact of anemia is gender dependent, based on the WHO and BW arbitrary criteria, suggesting differing mechanism and responses.

To investigate the association between heart rate recovery (HRR) and new-onset atrial fibrillation (AF) in middle-aged adults.Heart rate recovery was calculated using the exercise stress test in 15,729 apparently healthy self-referred men and women who attended periodic health screening examinations between January 2000, and December 2015. All participants completed the maximal exercise stress test according to the Bruce protocol and were followed clinically on a yearly basis for a median of 6.4±4 years. The primary end point was new-onset AF. Participants were grouped according to HRR at 5 minutes, dichotomized at the median value (73 beats/min).Participants with low HRR were older, were more commonly men, had a higher rate of comorbidities, and were less fit. Kaplan-Meier survival analysis revealed that the cumulative probability of AF at 6 years was higher in participants with low HRR (2.1%) than in those with high HRR (0.6%) (log-rank, P.001). Older age, male sex, obesity resting heart rate, and ischemic heart disease were all associated with increased AF risk in a univariate Cox regression model (P.05 for all). Multivariate Cox regression analysis revealed that low HRR was independently associated with increased AF risk (hazard ratio, 1.92; 95% CI, 1.3-2.8; P.001) after adjustment for multiple confounders.Lower HRR is independently associated with the development of new-onset AF during long-term follow-up in middle-aged adults.

Aims The SCORE risk estimation system is used for cardiovascular risk stratification in apparently healthy adults and is based on known cardiovascular risk factors. The purpose of the current study was to evaluate whether exercise capacity can improve the accuracy of the SCORE overall survival risk estimation. Methods and results We investigated 22 878 asymptomatic men and women who were annually screened in a tertiary medical centre. All subjects were free of known ischaemic heart disease, and had completed maximal exercise stress test according to the Bruce protocol. The SCORE risk estimation system was used to evaluate individual cardiovascular risk for all subjects. The primary endpoint was mortality, after exclusion of patients with metastatic cancer during follow-up. The incremental contribution of exercise capacity in predicting the risk of death was evaluated by net reclassification improvement (NRI) and area under the receiver operating curve (AUROC). Mean age of the study population was 47.4 ± 10.3, and 71.6% were men. There were 505 (2.21%) deaths during a mean follow-up of 9.2 ± 4.1 years. Kaplan–Meier survival analysis showed that both SCORE and low exercise capacity were associated with reduced survival. When added to the SCORE risk prediction, exercise capacity allowed more accurate risk stratification: NRI analysis showed an overall improvement of 56.8% in the accuracy of classification and the AUROC increased (0.782 vs. 0.766). Conclusion Both SCORE and exercise capacity are strong independent predictors of all-cause mortality. The addition of exercise capacity to the SCORE risk model can improve the accuracy of the model.

Guillain-Barré syndrome (GBS) is an autoimmune disease of the peripheral nervous system with a typical presentation of acute paralysis and hyporeflexia. Intravenous immunoglobulin (IVIG) and plasma exchange (PLEX) are treatments that have proven to expedite recuperation and recovery of motor function.To describe our experience at one tertiary medical center treating GBS with IVIG and to compare the efficacy of IVIG as the sole treatment versus combined therapy of IVIG and plasma exchange.We reviewed the records of all patients diagnosed with GBS and treated with IVIG at the Sheba Medical Center from 2007 to 2015 and collected data on patient demographics, disease onset and presentation, and treatments delivered. The motor disability grading scale (MDGS) was used to evaluate the motor function of each patient through the various stages of the disease and following therapy.MDGS improvement from admission until discharge was statistically significant (P0.001), as was the regainment of motor functions at 3 and 12 months follow-up compared to the status during the nadir of the disease. The effectiveness of second-line treatment with IVIG following PLEX failure and vice versa was not statistically significant (P0.15).The majority of patients included in this study experienced a significant and rapid improvement of GBS following treatment with IVIG. Combined therapy of PLEX and IVIG was not proven to be effective in patients who encountered a failure of the first-line treatment.

Obesity and overweight are strongly associated with cardiovascular morbidity and mortality. However, there are limited data on the association between excess weight and the risk of ectopic ventricular activity.We investigated the association between body mass index (BMI) and the risk for ectopic ventricular activity (defined as multiple ventricular premature beats (≥3), ventricular bigeminy, nonsustained ventricular tachycardia or sustained ventricular tachycardia) during exercise stress testing among 22,516 apparently healthy men and women who attended periodic health screening examinations between the years 2000 and 2014. All subjects had completed maximal exercise stress testing annually according to the Bruce protocol. Subjects were divided at baseline into three groups: normal weight (BMI ≥ 18.5 kg/m(2) and25; N = 9,994), overweight (BMI ≥ 25 and 30; N = 9,613) and obese (BMI ≥ 30; N = 2,906).The mean age of study subjects was 47 ± 10 years and 72% were men. Kaplan-Meier survival analysis showed that the cumulative probability for the development of exercise-induced ectopic ventricular activity arrhythmias was highest among obese subjects, intermediate among overweight subjects and lowest among subjects with normal weight (3.4%, 2.7% and 2.2% respectively; p 0.001). Multivariate binary logistic regression with repeated measures of 92,619 ESTs, showed that obese subjects were 33% more likely to have ectopic ventricular arrhythmias during exercise compared with subjects with normal weight (p = 0.005), and that each 1 kg/m(2) increase in BMI was associated with a significant 4% (p = 0.002) increased adjusted risk for exercise-induced ventricular arrhythmias.Obesity is independently associated with increased likelihood of ectopic ventricular arrhythmia during exercise.

Background: Several studies in animal models and human with obstructive sleep apnea syndrome (OSAS) demonstrated an increase in cancer aggressiveness and mortality. However, there is a need for further clinical evidence supporting a correlation between OSAS and cancer incidence. Objectives: To reveal whether OSAS presence and severity is correlated with cancer incidence in a large homogenous patients’ cohort. Methods: We analyzed a cohort of over 5,000 concurrently enrolled patients, age > 18, with suspected OSAS, from a tertiary medical academic center. Patients underwent whole night polysomnography, the gold standard diagnostic tool for OSAS, and were classified for severity according to the Apnea Hypopnea Index (AHI). Data on cancer incidence were obtained from the Israel National Cancer Registry. A multivariate Cox proportional-hazards analysis, adjusted for age, gender, and BMI, was performed to estimate the hazard-ratio of new cancer incidence. Results: Among 5,243 subjects with a median follow-up of 5.9 years, 265 were diagnosed with cancer. The most prevalent cancers were prostate (14.7%), hematological (12.8%), urothelial (9.4%), colorectal (9%), and breast (8.3%). In subjects who were diagnosed at age below 45 years (n = 1,533), a high AHI (> 57/h) was significantly associated with cancer (HR 3.7, CI 1.12–12.45, p = 0.008). Conclusions: Patients younger than 45 with severe OSAS have a significantly higher all-type cancer incidence than the general population. These results should encourage clinicians to detect and diagnose young patients with suspected OSAS and to recommend cancer screening methods in this high-risk population.

Intravenous immunoglobulins (IVIG) are a biologic product originally developed to treat immunocompromised patients. In the past decades, there has been increased utilization of IVIG in autoimmune conditions. The objectives were to evaluate the clinical use of IVIG in the largest tertiary medical center in Israel and to determine top uses, estimate off-label usage, and assess consumption of this blood product.We conducted an observational, retrospective study involving all patients who received IVIG from 2007 through 2015. Subjects were classified into five groups according to the indication for treatment.A total of 1117 patients were identified. The mean (±SD) ages of adults and children were 55 ± 17 and 8 ± 7 years, respectively. Most common indication for treatment were immune-mediated conditions (54%), followed by secondary immunodeficiency (28%), primary immunodeficiency (10%), infections (4%), and miscellaneous (4%). The main immune-mediated conditions treated were hematologic disorders (305 patients, 27%), neurologic disorders (219 patients, 20%), and rheumatologic conditions (79 patients, 7%). Overall, a significant change in study period was observed in the number of patients (p 0.001), consumption of IVIG (p 0.01), and amount of IVIG administered per patient (p 0.01). Fifty-six percent of the IVIG infusions were given for off-label Food and Drug Administration (FDA) indications.In this study, we demonstrated that immune-mediated conditions represent the majority of indications for treatment with IVIG. We observed a 417% increase in IVIG administration (g) over time, attributed mainly to autoimmune diseases. Many indications are still off-label according to FDA recommendations.

Anti-BLyS treatment with the human belimumab monoclonal antibody was shown to be a safe and effective therapeutic modality in lupus patients with active disease (i.e., without significant neurological/renal involvement) despite standard treatment.To evaluate the "real-life" safety and efficacy of belimumab added to standard therapy in patents with active lupus in five Israeli medical centers.We conducted a retrospective open-labeled study of 36 lupus patients who received belimumab monthly for at least 1 year in addition to standard treatment. Laboratory tests (C3/C4, anti dsDNA autoantibodies, chemistry, urinalysis and complete blood count) were done every 3-4 months. Adverse events were obtained from patients' medical records. Efficacy assessment by the treating physicians was defined as excellent, good/partial, or no response.The study group comprised 36 lupus patients (8 males, 28 females) with a mean age of 41.6 } 12.2 years. Belimumab was given for a mean period of 2.3 } 1.7 years (range 1-7). None of the patients discontinued belimumab due to adverse events. Four patients (11.1%) had an infection related to belimumab. Only 5 patients (13.9%) stopped taking belimumab due to lack of efficacy. The response was excellent in 25 patients (69.5%) and good/partial in the other 6 (16.6%). Concomitantly, serological response (reduction of C3/C4 and anti-dsDNA autoantibodies) was also observed. Moreover, following belimumab treatment, there was a significant reduction in the usage of corticosteroids (from 100% to 27.7%) and immunosuppressive agents (from 83.3% to 8.3%).Belimumab, in addition to standard therapy, is a safe and effective treatment for active lupus patients.

Data regarding travelers with chronic illnesses (TCI) traveling to developing countries is limited.A retrospective cohort study of travelers. We analyzed demographics, travel destinations, travel dates and duration, as well as the medical history (chronic illnesses, chronic medications, and allergies) of the travelers.Of 16,681 travelers evaluated, 3046 (18%) were TCI, of who, 2221 (13%) were taking chronic medications. The percentage of TCI ranged from 4% in the first decade of life to 65% in the 8th decade. The highest number of TCI (1085) was among the 20–30 years age group. The median age (IQR) of TCI was 39.0 (23.1–58.2), compared to 24.2 (22.0–32.1) years, of healthy travelers (p0.001). The major pre-existing medical conditions among TCI were endocrine/metabolic (38%), cardiovascular (26%) and pulmonary illnesses (16%). Within age groups, no difference was found in itinerary and other travel characteristics. However, 20–30 years old TCI, who were using chronic medications had significantly shorter travel duration (P0.001).TCI form a significant proportion of travelers among all age groups and travel destinations. Chronic illnesses appear to have little impact on travel itinerary and characteristics, but chronic medication use is associated with shorter travel duration to developing countries.

Smoking is an independent cardiovascular risk factor and correlates with reduced exercise tolerance. However, data on the time dependent effect of smoking cessation on exercise tolerance are limited.We investigated 17,115 men and women who were annually screened at the Institute for Medical Screening of the Chaim Sheba Medical Centre. All subjects had their smoking status documented and performed an exercise stress testing (EST) according to Bruce protocol at each visit. Subjects were divided at baseline into four groups: active smokers (N = 2858), recent quitters (smoking cessation ≤2 years before baseline EST; N = 861), remote quitters (smoking cessation2 years before the baseline EST; N = 3856) and never smokers (N = 9810). Baseline and follow up EST duration were compared among the four groups.Recent quitters demonstrated a 2.4-fold improvement in their EST duration compared with active smokers (improvement of 24 ± 157 vs. 10 ± 157 s, respectively, p = 0.02). Multivariate logistic regression showed that recent quitters were 26% more likely to improve their exercise tolerance compared with active smokers (95% confidence interval (CI) 1.08-1.47, p = 0.003). Assessing smoking status as a time-dependent covariate during four consecutive visits demonstrated that recent quitters were 17% more likely to improve their exercise tolerance compared with active smokers (95% CI 1.02-1.34, p = 0.02), with a less pronounced benefit among remote quitters (hazard ratio = 1.11, 95% CI 1.02-1.21; p = 0.01).Smoking cessation is independently associated with improved exercise tolerance. The benefits of smoking cessation are evident within the first two years of abstinence.

High-density lipoprotein cholesterol (HDL-C) is a strong inverse predictor of cardiovascular events. The aim of the current study was to evaluate the correlation between changes in HDL-C and subsequent cardiovascular events.Study population comprised 13,037 subjects free of cardiovascular disease with a mean follow up of 6 ± 3 years. Low HDL-C was defined as40 mg/dl for men and50mg/dl for women. Participants were divided into three groups based on HDL-C levels at the first and second baseline visits: persistently-low HDL-C (LL); persistently-high HDL-C (HH); and those with high HDL-C in a one visit only: intermittently high HDL-C (LH/HL). The primary endpoint was the first occurrence of a cardiovascular event.A total of 529 (4.1%) incident events occurred during follow-up. HDL-C levels increased significantly between the two landmark visits (47.5 ± 12.6 vs. 48.1 ± 12.2, p0.001). Kaplan-Meier survival analysis showed that the cumulative probability of cardiovascular events at 6 years was highest among subjects in the LL group (7.6%), and similar among LH/HL and HH groups (3.3% and 4%, respectively; log-rank p=0.001). Multivariate Cox regression analysis, with HDL-C as time-dependent covariate, showed that subjects with persistently low HDL-C during follow up experienced a 51% increased cardiovascular risk compared with subjects with persistently high HDL-C (p=0.026). Subjects with intermittently high HDL-C during follow up experienced similar risk to those with persistently high HDL-C (HR=1.02; p=0.89).Variations in HDL-C levels during follow-up are associated with subsequent cardiovascular risk. Patients who retain low HDL-C levels are at the cardiovascular highest risk.

Attenuated heart rate (HR) response during exercise is associated with adverse cardiovascular outcome. The acceptable value for HR response is 85% of the age-predicted maximal HR (APMHR). This study hypothesized that mild attenuation of HR response during exercise among healthy subjects is associated with increased cardiovascular risk. The study population comprised 10,323 healthy men and women without known cardiovascular disease (CVD) or diabetes mellitus who underwent a yearly screening program and were followed up during a mean period of 4.3 years. Participants were grouped to 3 tertiles based on the percentage of their APMHR reached at the baseline stress test. The primary end point was the occurrence of CVD or cerebrovascular disease. A total of 1,015 incident cases of CVD occurred during follow-up. A multivariate Cox proportional hazards regression model showed that the CVD risk of subjects who reached 60% to 96% of their APMHR was 35% greater compared with those who reached their APMHR (p = 0.001). A subgroup analysis among subjects who reached 85% of their APMHR showed that even mildly attenuated heart response (in the range of 85% to 96% APMHR) was independently associated with 36% increase in CVD risk (p0.001). In conclusion, attenuated HR response during exercise is a powerful and independent predictor of adverse cardiovascular events during long-term follow-up among healthy men and women. The prognostic implications of attenuated HR response in this population are apparent even with a minor decrease of the maximal HR to96% of the APMHR.

The identification of antinuclear antibodies (ANA) is an essential step in the diagnosis of different autoimmune diseases. The gold standard method for their detection is immunofluorescence assay. However, this is a subjective and laborious method, thus a need for simplified objective methods has aroused. In the current work, we evaluated such automated method, the LIAISON(®) (DiaSorin, Italy) for the detection of ANA. A total of 242 sera were analyzed including 67 from healthy subjects, 107 from primary biliary cirrhosis (PBC) patients, 20 from scleroderma patients and 48 from patients with Sjögren's syndrome. All sera were analyzed using the automated chemiluminescent immunoassays, LIAISON(®) for the presence of ANA (kit No. 310300). Positive samples were further analyzed for the presence of antidouble-stranded DNA (dsDNA) and autoantibodies to 6 extractable nuclear antigens (ENA) of the LIAISON(®) (kits No. 310330 and 310331). Negative samples were further analyzed by Blueblot ANA assay (D-TEK, Belgium) or BlueDot Liver (D-TEK, Belgium) as appropriate. The LIAISON(®) specificity for ANA screening was 97%. ANA positivity was determined in 80% of all patients. The sensitivity was 95.5% in scleroderma, 83% in PBC and 72.9% in Sjogren's syndrome. ENA was positive in all ANA-positive scleroderma and Sjögren's sera and in 27% of ANA-positive PBC sera. Among scleroderma or Sjögren patients that were ANA negative, 4 samples were positive for anti-SSA and 2 for RNP-68 utilizing Blueblot assays. M2 protein was found in 1 out of the ANA-negative PBC patients. The LIAISON(®) ANA screen is specific and sensitive for the evaluation of ANA in patients with primary biliary cirrhosis, scleroderma and Sjögren's syndrome.

Rheumatoid Arthritis (RA) is an autoimmune destructive joint disease affecting 1 % of the general population. In recent years, the benefits of identifying RA at an early stage and initiating therapy before joint damage occurs have been acknowledged. An elevated anti-citrullinated peptide antibody (ACPA) level serves as a marker for the early diagnosis of RA. Often the diagnosis is delayed because conventional methods of antibody detection require referral to a specific laboratory. In the current study, we determined the diagnostic accuracy of a new lateral flow point-of-care kit available for ACPA detection in the rheumatologist office. The presence of ACPA was determined by the visually read, qualitative rapid CCPoint

Background Metabolic syndrome and its components are severe global health issues that are increasing in frequency as the prevalence of obesity increases. Various studies have established a correlation between metabolic syndrome and diseases including, diabetes mellitus, non-alcoholic fatty liver disease, cirrhosis, and cardiovascular disease. In recent years, correlations have also been detected between obesity and metabolic syndrome and the prevalence of certain types of cancer. The current study examines whether obesity and metabolic syndrome components are risk factors for cancer among the adult population in Israel. Methods A cohort study analysis was performed of 24,987 initially healthy men and women who underwent yearly medical assessments at the Institute for Medical Screening in the Sheba Medical Center. Data from the Institute for Medical Screening database was correlated with that from the Israel Cancer Center in the Ministry of Health updated to December 2013. The correlation between metabolic syndrome, obesity, and the overall risk of cancer as well as the risks of specific types of cancer were examined. Results Of 20,444 subjects for whom complete data were available, 1535 were diagnosed with cancer during the mean follow-up time of 104.3 months. In a multi-variant analysis, no significant correlation was found between metabolic syndrome or obesity and the incidence of cancer. When the data were stratified by gender and cancer type, however, a significant association between metabolic syndrome and breast cancer in women was observed (P = 0.03, HR = 1.67, 95% CI = 1.05–2.67). Conclusion Metabolic syndrome correlates with higher than expected breast cancer incidence in women.

Men tend to develop cardiovascular disease (CVD) earlier in life than women. Whether this difference is attributable only to gender is a matter of debate. The purpose of this study was to evaluate gender differences in cardiovascular risk in a large cohort of asymptomatic men and women and explore gender-related risk in prespecified risk factor subgroups. We investigated 14,966 asymptomatic men and women free of diabetes, hypertension, or ischemic heart disease who were annually screened. The primary end point of the present study was the occurrence of ischemic or cerebrovascular disease as composite end point. Multivariate Cox proportional hazards regression modeling was used to assess the gender difference regarding CVD and to examine the association between CVD risk factors and gender. Mean age of the study population was 47 ± 10 years and 30% were women. Kaplan-Meier survival analysis showed that at 6.2 ± 3.9 years' follow-up, the rate of CVD events was 6.1% among men compared with 1.8% among women (log-rank p0.001). Consistently, multivariate analysis demonstrated that male gender was independently associated with a significant threefold increased risk for development of CVD events (hazard ratio 3.05, CI 2.25 to 4.14). The CVD risk associated with male gender was consistent in each risk subset analyzed, including older age, low high-density lipoprotein, impaired fasting glucose, and positive family history for ischemic heart disease (all p values for gender-by-risk factor interactions0.05). Higher performance on treadmill test had a protective effect regarding CVD development in both men and women. In conclusions, healthy middle-aged men experienced increased risk for the development of CVD events compared with women independently of traditional CVD risk factors. However, better exercise capacity is associated with a protective effect.

Serum lactate dehydrogenase (LDH) is known pathologic marker for a diversity of diseases, including myocardial ischemia. Strenuous and enduring physical activity can transiently induce a greater total LDH level, still within its normal range. To date, however, it has not been determined whether normal-range LDH might be inversely associated with coronary artery disease (CAD) in the low-cardiovascular-risk, physically active, adult population. We conducted a retrospective cohort analysis. A total of 5,519 healthy adults aged 34 to 86 years were followed up for a mean period of 4.2 years. The cohort incidence of CAD was 6.1% (338 cases) from 2001 to 2009. In the present cohort, greater mean LDH levels were significantly associated with a greater number of years, days/week, and minutes/week of leisure time activity (p = 0.02, p = 0.04, and p = 0.01, respectively). These associations were externally validated successfully by analysis of all 5,064 healthy participants aged ≥40 years with normal-range LDH from the 2007 to 2010 National Health and Nutrition Examination Surveys combined. For instance, the mean LDH level was significantly greater in those engaged in 6 to 7 versus 1 to 5 days/wk of vigorous-intensity work activity (138.0 ± 20.7 IU/L vs 133.3 ± 21.7 IU/L, respectively, p = 0.007). In our cohort, the hazard ratio for CAD according to the normal total serum LDH tertiles, adjusted for multiple risk and protective CAD factors in a Cox proportional hazards model, was 0.70 (95% confidence interval 0.54 to 0.92) in the greater versus lower tertile (p for trend = 0.01). In conclusion, we suggest that increased normal-range total serum LDH is associated with reduced short-term risk of CAD outcome in this low-risk, physically active population.

Autoantibodies (AAb), especially antinuclear (ANAs) and anticytoplasmatic antibodies (ACyA), are essential diagnosing markers for several autoimmune diseases. The current gold standard method for ANA detection is manual indirect immunofluorescence (IIF) on human epithelial-2 (HEp-2) cells. However, this technique is cost and time consuming, and characterized by considerable intra- and interlaboratory variability. Thus, an automated IIF-HEp-2 reader has been developed recently. In the current study, we compared the performance of the automated AAb IIF-HEp-2 interpretation to conventional detection methods. Autoantibody detection by IIF on HEp-2 cells was performed in a total of 260 sera of patients, including 34 with systemic lupus erythematosus, 111 with dermatomyositis or polymyositis, 74 with systemic sclerosis, 41 with rare AAb patterns, and 137 healthy individuals. Visual interpretation and routine immunoassays were compared with a novel automated IIF-HEp-2 system using Aklides pattern recognition algorithms. Positive AAbs were detected in 95-100% of rheumatic patients by automated interpretation, in 74-100% with manual reading, and in 64-100% by immunodot assay. Receiver operating characteristic curve analysis of fluorescent intensity revealed a high sensitivity and specificity for automated reading of AAb with an agreement ranging from 90% to 95% between manual and automated interpretation (kappa 0.554-0.69) for systemic sclerosis and myositis, respectively. This study demonstrates a good correlation between manual and automated interpretation of AAb including ANA and ACyA in patients with autoimmune diseases. Full automation of HEp-2 cell assay reading may minimize errors in ANA pattern interpretation and thus help in the standardization of ANA assessment.

ObjectivesThe importance of β2-glycoprotein I (β2GPI)-specific CD4+ T cells in the development of pathogenic processes in patients with antiphospholipid syndrome (APS) and APS mouse models is well established. Therefore, our objective is to manipulate the β2GPI specific CD4+ T cells using tolerogenic dendritic cells (tDCs) to induce tolerance. We aim to evaluate the capability of tDCs to induce antigen-specific tolerance in effector/memory T cells from patients with APS and to elucidate the involved mechanism.MethodsDCs and tDCs were produced from patients with APS peripheral-blood-monocytes, using specific cytokines. β2GPI-specific tolerance induction was investigated by coculturing control DC (cDC) or tDC, β2GPI-loaded, with autologous effector/memory T cells, evaluating the proliferative response, phenotype, cytokines secretion, viability and regulatory T cells.ResultsHuman monocyte-derived DCs treated with interleukin (IL)-10 and transforming growth factor β-1 (10/TGF-DC) induced β2GPI-specific-unresponsiveness in effector/memory CD4+ T cells (46.5%±26.0 less proliferation) in 16 of 20 analysed patients with APS, without affecting the proliferative response to an unrelated candidin. In five analysed patients, 10/TGF-DC-stimulated T cells acquired an IL-2lowinterferon γlowIL-10high cytokine profile, with just a propensity to express higher numbers of Foxp3+CTLA-4+ cells, but with an evident suppressive ability. In four of 10 analysed patients, 10/TGF-DC-stimulated T cell hyporesponsiveness could not be reverted and showed higher percentages of late apoptosis, pConclusionsThe inherent tolerance induction resistance of activated T cells present during the development of autoimmune diseases has delayed the application of tDC as an alternative therapy. This study highlights the 10/TGF-DC feasibility to induce antigen-specific unresponsiveness in autoreactive T cells generated in patients with APS by inducing apoptosis or T cells with regulatory abilities.

Rationale : The ubiquitin proteasome system (UPS) becomes dysfunctional as a result of ischemia/reperfusion (I/R), which may lead to dysregulation of signaling pathways. Ischemic preconditioning (IPC) may prevent dysregulation by preventing UPS dysfunction through inhibition of oxidative damage. Objective : Examine the hypothesis that early IPC preserves postischemic UPS function thus facilitating prosurvival signaling events. Methods and Results : I/R decreased proteasome chymotryptic activity by 50% in isolated rat heart and an in vivo murine left anterior descending coronary artery occlusion model. Following IPC, proteasome activity was decreased 25% ( P P P P Conclusions : These studies suggest that IPC protects function of the UPS by diminishing oxidative damage to 19S regulatory particle subunits allowing this complex to facilitate degradation of proapoptotic proteins.

Background The aim of the present study was to examine whether exercise blood pressure can be used to predict the development of hypertension in normotensive middle‐aged adults. Methods and Results We investigated 7082 normotensive subjects who were annually screened in a tertiary medical center and completed maximal treadmill exercise tests at each visit. After the initial 3 years, subjects were divided into approximate quartiles according to their average exercise systolic and diastolic blood pressure responses (≤158; 158 to 170; 170 to 183; ≥183 mm Hg for systolic blood pressure and ≤73; 73 to 77; 77 to 82; ≥82 mm Hg for diastolic blood pressure). Mean age of the study population was 48±9 years and 73% were men. Average baseline resting blood pressure was 120/77±12/7 mm Hg. During a follow‐up of 5±3 years, 1036 (14.6%) subjects developed hypertension. The cumulative probability of new‐onset hypertension at 5 years was significantly increased with increasing quartiles of exercise systolic blood pressure (5%, 9%, 17%, and 35%, respectively; P P P Conclusions In normotensive middle‐aged individuals, blood pressure response to exercise is associated with future development of hypertension.

Increased body mass index (BMI) and obesity are associated with increased risk of new-onset atrial fibrillation (AF) among middle-aged adults.The objective of the study is to investigate the association between BMI and the risk for new-onset AF among middle-aged adults.We investigated 18,290 men and women who were annually screened in a tertiary medical center. Participants were divided at baseline into 3 groups: normal weight (BMI ≥18 and25 kg/m(2), n = 7,692), overweight (BMI ≥25 and30 kg/m(2), n = 8,032), and obese (BMI ≥30 kg/m(2), n = 2,566). The primary end point was new-onset AF during follow-up.Mean age of study population was 49 ± 11 years, and 73% were men. A total of 288 incident events (1.6%) occurred during 6 ± 4 years. Kaplan-Meier survival analysis showed that the cumulative probability of AF at 6 years was highest among obese participants, intermediate among overweight participants, and lowest among participants with normal weight (2.1%, 1.7%, and 0.8% respectively, P.001). Multivariable Cox regression analysis showed that overweight and obesity were independently associated with increased AF risk (hazard ratio 1.54 [P = .004] and 2.41 [P.001], respectively). Assessment of BMI change as a time-dependent covariate in the multivariable model showed that each 1 kg/m(2) reduction in BMI during follow-up was associated with a significant 7% reduction in the risk for the occurrence of a first AF event (hazard ratio 0.93, 95% CI 0.88-0.99, P = .019). Consistently, similar analysis showed that each 5-kg weight loss during follow-up was independently associated with a significant 12% reduced risk of new-onset AF (95% CI 0.81-0.98, P = .02).Our findings suggest that overweight and obesity are associated with increased AF risk, whereas weight reduction is independently associated with reduced risk of de novo AF.

The role of the proapototic Bax gene in ischemia-reperfusion (I/R) injury was studied in three groups of mice: homozygotic knockout mice lacking the Bax gene (Bax−/−), heterozygotic mice (Bax+/−), and wild-type mice (Bax+/+). Isolated hearts were subjected to ischemia (30 min, 37°C) and then to 120 min of reperfusion. The left ventricular developed force of Bax-deficient vs. Bax+/+ hearts at stabilization and at 120 min of reperfusion was 1,411 ± 177 vs. 1,161 ± 137 mg and 485 ± 69 vs. 306 ± 68 mg, respectively. Superior cardiac function of Bax−/− hearts after I/R was accompanied by a decrease in creatine kinase release, caspase 3 activity, irreversible ischemic injury, and the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cardiomyocytes. Electron microscopic evaluation revealed reduced damage to mitochondria and the nuclear chromatin structure in Bax-deficient mice. In the Bax+/− hearts, the damage markers were moderate. The superior tolerance of Bax knockout hearts to I/R injury recommends this gene as a potential target for therapeutic intervention in patients with severe and intractable myocardial ischemia.

The objectives of this study were to gather information regarding demographic and clinical characteristics of patients diagnosed with either fibromyalgia (FM) or chronic fatigue (CFS) following hepatitis B vaccination (HBVv) and furthermore to apply the recently suggested criteria of autoimmune (auto-inflammatory) syndromes induced by adjuvants (ASIA), in the aim of identifying common characteristics that may suggest an association between fibromyalgia, chronic fatigue and HBV vaccination. Medical records of 19 patients with CFS and/or fibromyalgia following HBVv immunization were analyzed. All of which were immunized during 1990-2008 in different centers in the USA. All medical records were evaluated for demographics, medical history, the number of vaccine doses, as well as immediate and long term post-immunization adverse events and clinical manifestations. In addition, available blood tests, imaging results, treatments and outcomes were analyzed. ASIA criteria were applied to all patients. The mean age of patients was 28.6 ± 11 years, of which 68.4 % were females. 21.05 % had either personal or familial background of autoimmune disease. The mean latency period from the last dose of HBVv to onset of symptoms was 38.6 ± 79.4 days, ranging from days to a year. Eight (42.1 %) patients continued with the immunization program despite experiencing adverse events. Manifestations that were commonly reported included neurological manifestations (84.2 %), musculoskeletal (78.9 %), psychiatric (63.1 %), fatigue (63.1 %), gastrointestinal complains (58 %) and mucocutaneous manifestations (36.8 %). Autoantibodies were detected in 71 % of patients tested. All patients fulfilled the ASIA criteria. This study suggests that in some cases CFS and FM can be temporally related to immunization, as part of ASIA syndrome. The appearance of adverse event during immunization, the presence of autoimmune susceptibility and higher titers of autoantibodies all can be suggested as risk factors. ASIA criteria were fulfilled in all patients eluding the plausible link between ASIA and CFS/FM.

Vitamin D immune-modulating effects were extensively studied, and low levels have been linked with autoimmune diseases. The associations of vitamin D with autoimmune diseases of the liver, and particularly primary biliary cirrhosis (PBC), are yet to be defined. Hence, in this study, serum levels of vitamin D were determined in 79 patients with PBC and 70 age- and sex-matched controls by the LIAISON chemiluminescent immunoassays (DiaSorin-Italy). Clinical and serological parameters of patients were analyzed with respect to vitamin D status. Mean levels of vitamin D were significantly lower among patients with PBC compared with controls (16.8 ± 9 vs. 22.1 ± 9 ng/ml; p = 0.029), and vitamin D deficiency (≤10 ng/ml) was documented in 33% of patients with PBC versus 7% of controls (p < 0.0001). Vitamin D levels inversely correlated with advanced liver damage and the presence of concomitant autoimmune diseases. In contrast, higher levels of vitamin D were observed among patients with PBC treated with ursodeoxycholic acid (UDCA). In conclusion, low vitamin D levels are common among patients with PBC and correlate with advanced disease, lack of UDCA therapy and autoimmune comorbidity. This alludes to the plausible roles of vitamin D as a prognostic marker of PBC severity, and as a potential player in this disease pathogenesis. While further studies are awaited, monitoring vitamin D in patients with PBC and use of supplements may be advisable.

Increased blood levels of alanine amino transferase (ALT, also known as SGPT; serum glutamic pyruvic transaminase) serve as a marker of liver injury by various mechanisms. Less is known about the clinical implications associated with low-normal ALT levels. Previous studies showed low ALT levels to be associated with poor long-term outcomes among elderlies, serving as a biomarker for increased incidence of frailty and subsequent risk of mortality. However, it has not been determined yet whether low-normal ALT values might be predictive of frailty and mortality in younger, middle-aged adults.We conducted a historical prospective cohort analysis.A total of 23,506 adults with ALT levels within the normal range, at the mean age of 48 ± 11 years, participating in an annual screening program for preventive medicine, were followed-up for a median period of 8.5 years during which 638 died. Low-normal ALT values (serum ALT activity17IU/L) were found to be predictive for increased risk of all-cause mortality (HR=1.6; 95% CI 1.34-1.92; p0.001). Statistically significant correlation was demonstrated even after applying a multifactorial model correction for age, gender, eGFR, low albumin, arterial hypertension, diabetes mellitus and ischemic heart disease.We suggest that low-normal ALT values may serve as an independent predictive marker for increased long-term mortality in middle-aged adults.

Background Human autoimmune myocarditis is characterized by an increased frequency of serum organ and disease-specific anti-heart autoantibodies (AHA) in affected patients. To assess whether AHA are directly pathogenic, we used the passive transfer technique of AHA from patients to normal Balb/c mice to induce an experimental myocarditis. Methods In keeping with a classical passive transfer experiment, sera from 5 AHA positive myocarditis patients (3 male, mean age 30±11years, 3 with giant cell and 2 with lymphocytic myocarditis) were affinity purified and injected into 25 Balb/c mice. As controls, affinity purified sera from 5 healthy donors were passively transferred to 25 Balb/c mice. Further 15 control mice were injected with phosphate-buffered saline and 9 mice did not receive any injection. In all patients cardiac-specific AHA of IgG class had been previously detected by an indirect immunofluorescence (IFL) technique on cryostat sections of O blood group human heart. The animals were sacrificed after 4weeks and the hearts were blindly examined for histological evidence of myocarditis by an expert cardiac pathologist. Results Myocarditis was present in 13/25 (52%) of the mice which received affinity-purified IgG from patients. The findings of severe, moderate or mild myocarditis were more common in the mice which received affinity-purified IgG from patients (20%; 20% and 12%) than in control animals (2%, p=0.01; 0%, p=0.003; and 0%, p=0.04 respectively). Conclusions These findings provide a new evidence for AHA-mediated pathogenicity in human myocarditis, according to Rose–Witebsky criteria.

Sjögren's syndrome (SS) is an autoimmune disease characterized primarily by lymphocytic infiltration of the exocrine glands, and autoantibody production. Multiple environmental factors affecting an individual with a genetic susceptibility may trigger the development of SS. Herein, we aimed to evaluate links between the different pebbles in the mosaic of SS. Demographic, clinical data and blood samples were gathered from 82 consecutive patients with SS, and 139 healthy controls. Samples were analyzed for infectious serology and auto-antibodies as well as for relevant genetic mutations (TAP genes) and cytokines levels. An immune response (IgG) against Epstein-Barr virus (EBV) early antigen (EA) was positively associated with SS (OR 4; 95% CI: 1.82-8.83, p=0.001) while a protective effect of IgG anti-cytomegalovirus (CMV) was observed (OR 0.3; 95%CI: 0.16-0.74, p=0.009). Anti-Ro/SSA, anti-LA/SSB, anti-nuclear, anti-gliadin, anti-TTG-IgG and anti-RNP antibodies were statistically more prevalent among SS patients than controls. Notably, the presence of anti-Ro/SSA and anti La/SSB correlated with anti-EBVEA IgG (OR 3.1; 95%CI: 1.08-8.74) and (OR 3.9; 95%CI: 1.37-10.96) respectively. Autoantibodies, cytokines and several genetic markers correlated with clinical manifestation of SS. Our data suggest that infectious agents may play both a causative and protective role in the pathogenesis of SS. Moreover certain autoantibodies, cytokines and specific TAP alleles correlate with clinical manifestations of SS, and may enable better prediction and/or directed therapy once confirmed in future studies. © 2014 Elsevier Ltd.

Allergic diseases have increased significantly in developed countries for reasons yet to be determined. We studied the epidemiology of bronchial asthma (B.A.) and chronic rhinitis (Ch.R.) among Israeli school children from two neighboring towns, one Jewish (Zichron Yaakov, school population = 585) and the other Arab (Paradis, school population = 658). The children (age range 8-17 years, 567 males, 676 females) shared the same climate and had similar demographic characteristics. They received similar medical care and had the same rates of hospitalization and emergency room visits. The Jewish children had a higher prevalence of B.A. (13.7% vs. 9.4%), Ch.R. (19.7% vs. 9.7%), and stuffy nose (31% vs. 14%) than their Arab counterparts. In addition to ethnicity, parental smoking habits were the major differentiating factor between the two groups: 20% of the mothers and 29% of the fathers from Zichron Yaakov and 2% of the mothers and 60% of the fathers from Paradis were smokers. Smoking fathers increased the rate of B.A. in both towns as well as emergency room visits, but not the rate of Ch.R. or stuffy nose. A familial history of B.A. was the main determinant for having childhood asthma or chronic rhinitis. We conclude that in addition to family history and ethnicity, smoking among mothers was the major contributing factor for the higher prevalence of atopic diseases among Jewish schoolchildren compared to their Arab counterparts.

Data on differences in toxicity and efficacy of chemotherapy and radiotherapy among different ethnic groups is limited. We evaluated differences in toxicity, tolerability and clinical outcome of Ashkenazi and non-Ashkenazi Jews receiving postoperative chemoradiation for locally advanced gastric cancer (LAGC).Between 6/2000-12/2007, 84 Ashkenazi patients and 60 non-Ashkenazi patients underwent chemoradiation following resection of LAGC (INT-116 trial).Patients' and tumor characteristics were comparable. Ashkenazi patients experienced significantly higher rates of fatigue, anorexia, and grade 3-4 dysphagia, as well as a trend for a higher rate of diarrhea. The incidence of other toxicities, dose adjustments of chemotherapy and radiotherapy and patient prognosis did not differ.This study shows higher rates of various toxicities among Ashkenazi patients receiving postoperative chemoradiation for LAGC compared to non-Ashkenazi patients. To our knowledge, this is the first study comparing treatment toxicity, tolerability and outcome between these two groups.

Cardiac sympathetic denervation is an early nonmotor feature of Parkinson's disease (PD). The aim of the current study was to trace evidence for cardiac dysfunction abnormalities in the premotor phase of PD. We retrospectively reviewed treadmill ergometric tests of a large cohort (n = 16,841) between 2000 and 2012, that attended the Executive Screening Survey (ESS) at Sheba Medical Center. Heart rate and blood pressure profiles as well as exercise capacity were compared between subjects who later developed PD and age- and sex-matched subjects (ratio 1:2) who did not. We identified 28 subjects (24 males) who developed PD at follow-up. The PD group was older than the group of subjects who did not develop PD on first ergometric test (64.82 ± 8.82 vs. 48.91 ± 10.60 years, P 0.001). The time between the first ergometric test and motor symptoms onset was 4.64 ± 2.86 years. Patients who later developed PD had lower maximal heart rate (P 0.001) and lower heart rate reserve than healthy controls (P 0.001); however, compared with age- and sex-matched subjects, subjects who developed PD had similar exercise capacity and heart rate profile during rest, exercise, and recovery, even 1 year before diagnosis. In this study, we did not detect significant signs of sympathetic dysfunction during the premotor phase of PD.

Previous studies have demonstrated an association between increased serum uric acid (SUA) levels and incident diabetes. Most clinical and epidemiological investigations, however, focused solely on male populations or did not analyze men and women separately. We assessed the association between SUA levels and diabetes incidence in a large cohort of apparently healthy men and women.Data were retrospectively gathered from 9140 adults who participated in annual medical screening visits during 2000-2009. Mean follow-up time was 4.8 years, and the median age was 50 years. Laboratory test results, data from physical examinations, medical history, and lifestyle information were extracted. The main outcome measure was incident diabetes, defined as two consecutive fasting glucose tests higher than 125 mg/dL. Cox proportional-hazards multivariate models were applied for measuring hazard ratios (HRs) for diabetes according to continuous and categorical levels of uric acid.We identified 499 new cases of diabetes (total, 5.5%: men, 6.2%; women, 3.6%) during the follow-up period. The gender-specific HRs for diabetes, adjusted for age and a set of prespecified multiple risk and protective factors, were 1.57 for each 1 mg/dL increase in SUA (95% confidence interval [CI], 1.32-1.86) in women and 1.08 (95% CI, 0.99-1.17) in men; p for interaction of SUA by gender0.001.SUA is independently associated with diabetes outcome, considerably more in women than in men.

Clinical thyroid disease is associated with changes in the cardiovascular system, including changes in heart rate during exercise. However, data on the relation between subclinical thyroid disease (SCTD) and heart rate during exercise are limited.We investigated 3799 apparently healthy subjects who were evaluated in the Institute for Preventive Medicine at the Sheba Medical Center. All subjects answered standard health questionnaires; were examined by a physician; completed routine blood tests including thyrotropin, free triiodothyronine, and free thyroxine levels; and underwent a treadmill exercise according to the Bruce protocol. Subjects with known thyroid disease or those who were taking thyroid-related drugs were excluded from the analysis. Heart rate profile was compared between patients with subclinical hypothyroidism (SCHypoT), patients with normal thyroid function, and patients with subclinical hyperthyroidism (SCHyperT) using propensity score matching.Seventy patients had SCHyperT and 273 had SCHypoT. Compared with age- and sex-matched normal subjects, SCHyperT subjects had a higher resting heart rate (83±17 vs. 76±12 beats per minute [bpm], p=0.006), a significantly higher recovery heart rate (94±12 vs. 90±12 bpm, p=0.045), and a significantly lower heart rate reserve (80±20 vs. 87±18 bpm, p=0.006). Subjects with SCHypoT showed a trend toward a lower resting heart rate (75±13 vs. 77±15 bpm, p=0.09) and had a significantly lower recovery heart rate (88±12 vs. 90±13 bpm, p=0.035). There was no significant difference in exercise duration or blood pressure between subjects with SCTD and their matched normal controls.Subjects with SCTD have a significantly different heart rate profile during rest, exercise, and recovery.

Autoinflammatory attacks in familial Mediterranean fever (FMF) are accompanied by elevated levels of interleukin-6 (IL-6), and are controllable by IL-1-targeting drugs. In combination, IL-6 and IL-1 are known to be potent inducers of T helper (Th) 17 cells development. Therefore, we studied the Th17 population size, and activation potential, of FMF patients. Based on the relative mRNA expression of the Th1, Th2, Treg and Th17 transcription factors T-bet, GATA3, FOXP3 and retinoic acid-related orphan receptor γT (RORγT), respectively, the Th17 population in peripheral blood mononuclear cells (PBMCs) of healthy subjects was estimated at 2.5% of the entire Th population and 4.4% in FMF patients in remission (n=6 for each group, P=0.03). IL-17 secretion after universal stimulation of the T-cell receptor in PBMCs culture was twice higher in cultures of patients with frequent attacks (n=18) than in those of patients with infrequent attacks (n=10, 1124±266 vs 615±196 pg ml(-1), P=0.009). IL-17 secretion correlated well with IL17A mRNA level. Part of the increased secretion was related to the deleterious, MEFV p.M694V homozygous genotype (n=19, 1.5-fold, P=0.03). Almost all IL-17 producer cells were CD4-positive (CD4(+)IL-17(+)). In conclusion, frequent attacks and the deleterious FMF genotype appear to drive FMF patients to a heightened Th17 response.

Both resting blood pressure (BP) variability and exercise BP previously showed association with incident hypertension. The aim of the present study was to examine whether visit-to-visit variability in exercise systolic blood pressure (SBP) can predict the risk for new-onset hypertension among normotensive adults. We investigated 6546 normotensive men and women who were annually screened in a tertiary medical center and completed treadmill exercise tests at each visit. Based on the initial three baseline annual visits, long-term intervisit variability of exercise SBP among the three tests was measured using standard deviation (SD) and coefficient of variation for each participant. The rate of newly diagnosed hypertension was measured in different variability levels during 6 ± 3 years of follow-up. Multivariate analysis adjusted for various clinical factors, including resting BP, showed that each 5 mm Hg rise in the SD of exercise SBP resulted in a significant 5% increase in the risk for the development of future hypertension (P = .015). Subjects in the upper exercise SBP SD variability tertile had a 28% (P = .007) increased risk for hypertension during follow-up, as compared with those in the lowest tertile. Similar results were achieved for the assessment of coefficient of variation of exercise SBP. In conclusion, visit-to-visit variability in exercise SBP can predict the development of future hypertension among normotensive individuals.

While moderate and severe chronic kidney disease is an established independent risk factor for cardiovascular disease (CVD), the association of estimated glomerular filtration rate (eGFR) differences within the normal to mildly reduced range (from 60 to90 ml/min/1.73 m(2)) and CVD is less clear. Our aim was to examine the association of eGFR with incident CVD in a cohort of predominantly healthy subjects with normal to mildly reduced renal function.Retrospective cohort study.We collected demographic, clinical, and laboratory parameters of subjects free of diabetes mellitus or CVD who attended annual medical screening examinations between 2001 and 2009. Main outcome measures were a new diagnosis of coronary artery disease (CAD) or cerebrovascular events (CVE).During a median follow up of 4.3 years, among 10,909 subjects (mean eGFR 78.5 ± 12.2 ml/min/1.73 m(2)), 10.3% were diagnosed with CAD (n = 1025) or CVE (n = 94). Compared with subjects in the highest eGFR quintile (≥ 88.8 ml/min/1.73 m(2)), subjects in the lowest quintile (≤ 68.2 ml/min/1.73 m(2)) had a hazard ratio (HR) of 1.64 (95% CI 1.35-2.00; p0.001) for a CAD outcome, but this association was no longer significant after adjustment for age and other confounders (adjusted HR 1.08; p = 0.55). Similar findings were obtained for the association of eGFR with CVE.In a predominantly healthy population with normal to mildly reduced renal function, lower eGFR is associated with higher risk for CVD; however, this association is not independent but merely reflects the association of age and other cardiovascular risk factors with reduced eGFR.

Studies in different populations with high risk for cardiovascular disease (CVD) have shown an association between serum uric acid (SUA) and CVD. However, only a few studies have demonstrated such an association in healthy populations. The aim of this study was to investigate the association between SUA and CVD in a cohort of men and women without diabetes or CVD. A retrospective study was conducted, with a mean 4.8-year follow-up. The outcome was the occurrence of a cardiovascular event, defined as the diagnosis of ischemic heart disease, acute coronary syndrome, acute myocardial infarction, or ischemic stroke. Mean SUA levels were 6.2 ± 1.1 mg/dl for men (n = 6,580) and 4.4 ± 1.1 mg/dl for women (n = 2,559). For women, the rate of CVD occurrence was 11.6% for the highest quartile of SUA level, compared with 5.0% to 6.5% for the lower 3 quartiles. For men, the rate of CVD occurrence was 14.0% for the highest quartile of SUA level, compared with 10.8% for the lowest quartile. The hazard ratio for CVD, adjusted for age, serum creatinine level, body mass index, systolic blood pressure, low-density lipoprotein cholesterol level, triglyceride level, plasma fasting glucose, physical activity, cardiovascular family history, use of diuretics, and current smoking, was 1.24 (95% confidence interval 1.08 to 1.41) for women and 1.06 (95% confidence interval 1.00 to 1.13) for men (p for interaction = 0.04). In conclusion, the strong association of SUA levels with CVD in women, compared with the much lesser degree in men, highlights the necessity of stratifying by gender in investigations of cardiovascular risk factors and supports exploration of SUA as a marker of CVD risk in healthy populations.

Background/purpose Primary Sjogren’s syndrome (SS) is a chronic autoimmune disease primarily involving the exocrine glands. The clinical picture of SS ranges from exocrinopathy to systemic disease affecting the lung, kidney, liver, skin, musculockeletal and nervous systems. The morbidity of SS is mainly determined by extraglandular disease and increased prevalence of lymphoma. Environmental and hormonal factors, such as vitamin-D may play a role in the pathogenic process and disease expression. Thus, we aimed to evaluate levels of vitamin-D and their association with manifestations of SS. Methods Vitamin-D levels were determined in 176 primary SS patients and 163 matched healthy volunteers utilizing the LIAISON chemiluminescent immunoassays (DiaSorin-Italy). A correlation between vitamin-D levels and clinical and serological manifestations of SS was performed. Results Mean vitamin-D levels were comparable between SS patients and control 21.2 ± 9.4 ng/ml and 22.4 ± 10 ng/ml, respectively. Peripheral neuropathy was diagnosed in 23% of SS patients and associated with lower vitamin-D levels (18.6 ± 5.5 ng/ml vs. 22.6±8 ng/ml ( p = 0.04)). Lymphoma was diagnosed in 4.3% of SS patients, who had lower levels of vitamin-D (13.2 ± 6.25 ng/ml), compared to SS patients without lymphoma (22 ± 8 ng/ml), ( p = 0.03). Other clinical and serological manifestations did not correlate with vitamin-D status. Conclusions In this study, low levels of vitamin-D correlated with the presence of peripheral neuropathy and lymphoma among SS patients. The link between vitamin-D and neuropathy or lymphoma was reported in other conditions, and may support a role for vitamin-D in the pathogenesis of these processes. Plausible beneficial effect for vitamin-D supplementation may thus be suggested.

Amyloidosis of familial Mediterranean fever (FMF) may lead to end-stage renal failure, culminating in kidney transplantation in some patients.To assess demographic, clinical and genetic risk factors for the development of FMF amyloidosis in a subset of kidney-transplanted patients and to evaluate the impact of transplantation on the FMF course.Demographic, clinical and genetic data were abstracted from the files, interviews and examinations of 16 kidney-transplanted FMF amyloidosis patients and compared with the data of 18 FMF patients without amyloidosis.Age at disease onset and clinical severity of the FMF amyloidosis patients prior to transplantation were similar to FMF patients without amyloidosis. Compliance with colchicine treatment, however, was much lower (50% vs. 98%). Posttransplantation, FMF amyloidosis patients experienced fewer of the typical serosal attacks than did their counterparts (mean 2214 days since last attack vs. 143 days). Patients with FMF amyloidosis carried only M694V mutations in the FMF gene, while FMF without amyloidosis featured other mutations as well.Compliance with treatment and genetic makeup but not severity of FMF constitutes major risk factors for the development of amyloidosis in FMF. Transplantation seems to prevent FMF attacks. The protective role of immunosuppressive therapy cannot be excluded.

Amyloidosis of familial Mediterranean fever (FMF) may lead to end-stage renal failure, culminating in kidney transplantation. Since amyloidosis is prompted by high serum amyloid A (SAA) levels, increased SAA is expected to persist after transplantation. However, no data are available to confirm such an assumption.To determine SAA levels in kidney-transplanted FMF-amyloidosis patients and evaluate risk factors for the expected high SAA levels in this patient group.SAA, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) values were obtained from 16 kidney-transplanted FMF-amyloidosis patients, 18 FMF patients without amyloidosis and 20 kidney-transplanted patients with non-inflammatory underlying disease. Demographic, clinical and genetic risk factors evaluation was based on data extracted from files, interviews and examination of the patients.SAA level in FMF patients who underwent kidney transplantation due to amyloidosis was elevated with a mean of 21.1 +/- 11.8 mg/L (normalor = 10 mg/L). It was comparable to that of transplanted patients with non-inflammatory disorders, but tended to be higher than in FMF patients without amyloidosis (7.38 +/- 6.36, P = 0.08). Possible risk factors for the elevated SAA levels in kidney transplant patients that were excluded were ethnic origin, MEFV mutations, gender, age and disease duration.Kidney-transplanted patients with FMF-amyloidosis and with other non-FMF causes displayed mildly elevated SAA levels, possibly resulting from exposure to foreign tissue rather than from various FMF-related factors.

Hypovitaminosis D has been shown to be extremely common in various regions around the world, mostly at high latitudes. Israel is characterized by certain features--cultural (e.g., ethnic isolates) and geographic (e.g., sunny climate)--that have been identified for their possible association with vitamin D status.To conduct an ecological study on a representative sample of the population of Israel, testing vitamin D status across age groups, genders, ethnic groups, and seasons.We obtained serum samples from 195 heaIthy Israeli volunteers representing a broad demographic spectrum. Serum concentrations of 25(OH)D were measured with the commercial kit Liaison 25(OH)D Assay (DiaSorin, Italy).The mean vitamin D level for the entire cohort was surprisingly low (22.9 +/- 10.1 ng/ml), with 149 subjects (78%) suffering from vitamin D insufficiency (30 ng/lml). Vitamin D status was better in infants than in olderage groups. Differences by gender were significant only inthe infant age group (i.e., vitamin D status was worse among females) and were not prominent across older ages. Israelis of Ashkenazi origin had higher vitamin D mean levels than those of Sephardic origin, who, in turn, had higher vitamin D levels than Arab subjects (31.4 +/- 12, 24.1 +/- 10, and 17.6 +/- 9 ng/ml respectively). With regard to season, there were no differences between the samples collected in winter and the samples collected in summer.The results suggest that hypovitaminosis D is common across all ages, genders and seasons in Israel, a country characterized by a sunny Mediterranean climate. Specific ethnic groups may be at especially high risk.